SYNTHESIS AND ANTINEOPLASTIC PROPERTIES OF ETHER-LINKED THIOGLYCOLIPIDS

Ether-linked glycero-α- and β-D-glucopyranosides and glycero-1-thio-α- and β-D-glucopyranosides have been synthesized by modifications of the Konigs-Knorr procedure, and their antitumor activities have been evaluated. The bioactivities of these compounds have been evaluated in five different cell lines (WEHI 3B, C653, X63/OMIL3, R6X-B15, and HL-60) and compared with the activities of 1-O-hexadecyl-2-O-methyl-sn-3-glycerophosphocholine (GPC) and its enantiomer, 3-O-hexadecyl-2-O-methyl-sn-l-GPC. The results indicate that a a-D-thioglucopyranoside [1-O-hexadecyl-2-O-methyl-3-S-(α-D-1‘-thioglucopyranosyl-sn-glycerol)] is selective with respect to its action on target cells, with high activity for killing of WEHI 3B and C653 cells as determined by inhibition of [3H]thymidine incorporation into DNA and HL-60 cell cytotoxicity, but unable to induce aggregation of rabbit platelets at 10–5M. The corresponding β-linked thioglycolipid was ineffective with respect to cytotoxicity against each cell line tested, indicating the importance of configuration at the anomeric position; the β-thioglycoside was also ineffective with respect to inducing platelet aggregation. 1-O-Hexadecyl-2-O-methyl-sn-3-GPC and 3-O-hexadecyl-2-O-methyl-sn-1-GPC were potent inhibitors of growth of each cell line tested but also caused rabbit platelet aggregation at concentrations ≥ 10-7M. Thus, 3-S-(a-thioglycopyranosyl)-sn-glycerols bearing a long-chain O-alkyl group at the sn-1 position and a methoxy group at the sn-2 position of glycerol appear to be a promising class of antineoplastic agents with lower risk of inducing thrombosis than the widely studied platelet activating factor analogue, 1-O-octadecyl-2-O-methyl-rac-3-GPC. © 1990, American Chemical Society. All rights reserved.